Reduced reticulum–mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

Abstract

Type 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum–mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum–mitochondria interface revealed tighter interactions not compatible with Ca2+ transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca2+ sensors were performed to measure Ca2+ fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R–VDAC interaction and a reduced IP3-stimulated Ca2+ transfer to mitochondria, with no changes in reticular Ca2+ level, cytosolic Ca2+ transients, and mitochondrial Ca2+ uniporter function. Disruption of organelle Ca2+ exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca2+ transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum–mitochondria Ca2+ miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca2+ dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.

A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?

“…However, contrarily to these results, other studies propose heart failure to be associated with a reduced ER–mitochondria coupling: in diabetes type 2, where a reduced Ca 2+ shuttling in MAM regions was repeatedly demonstrated for many tissues [ 115 , 116 , 117 ], a reduction in IP3R-VDAC1 interaction and, thus, a decrease in IP3 stimulated Ca 2+ transfer to mitochondria was observed for cardiomyocytes. The impaired SR–mitochondrial Ca 2+ coupling resulted in an impairment of mitochondrial energy supply, reduced cell contraction, and thus, cardiomyopathy [ 118 ].…”

Novel Insight into the Role of Endoplasmic Reticulum Stress in the Pathogenesis of Myocardial Ischemia‐Reperfusion Injury

“…As a result of the ATP undersupply, the calcium pump within cardiomyocytes cannot effectively remove calcium from the cytoplasm, resulting into calcium overload [40,41]. The resultant abnormal calcium signal blunts ventricular contraction and promotes the development of cardiac dysfunction [42][43][44].…”

Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium

“…Subsequently, Ca 2+ is transported into the inner mitochondrial membrane by MCU to activate the pyruvate dehydrogenase complex for ATP synthesis. Reduced Ca 2+ transport into the mitochondria due to decreased IP 3 R-VDAC interaction is associated with mitochondrial dysfunction [ 196 ]. Interactions of Bcl-2 and Mcl-1 with all IP 3 R isoforms have been observed and are accompanied by increased Ca 2+ release and reduced apoptosis [ 197 ].…”